S Liu1, J Zha2, M Lei2. 1. Department of Ultrasound, The People's Hospital of Three Gorges University, The First People's Hospital of Yichang, Yichang, 443000, China. latte201217@163.com. 2. Department of Obstetrics and Gynecology, The People's Hospital of Three Gorges University, The First People's Hospital of Yichang, Yichang, 443000, China.
Abstract
PURPOSE: To investigate whether ERK/MNK/eIF4E contributes chemoresistance in ovarian cancer. METHODS: The phosphorylated levels of Erk, Mnk, and eIF4E were systematically analyzed in ovarian cancer patients before and after chemotherapy, and ovarian cancer cells exposed to short- and long-term chemo-agent treatment. The roles of Erk/Mnk/eIF4E were investigated using pharmacological and genetic approaches. RESULTS: Increased phosphorylation levels of ERK, Mnk1, and eIF4E were observed in ovarian cancer cell exposed to chemotherapeutic agents, and paclitaxel-resistant SK-OV-3-r cells, and is a common response of ovarian cancer patients undergoing chemotherapy. MEK inhibitor U0126 inhibits basal and chemodrug-induced phosphorylation of ERK as well as Mnk1 and eIF4E, suggesting that Mnk1/eIF4E are the downstream signaling of ERK pathway and chemotherapy agents activate ERK/MNK/eIF4E in a MEK-dependent manner. eIF4E overexpression promotes ovarian cancer cell growth without affecting migration. In addition, ovarian cancer cells with eIF4E overexpression are more resistant to chemotherapeutic agents in aspect of growth inhibition and apoptosis induction compared to control cells. In contrast, eIF4E depletion augments chemotherapeutic agents' effect in ovarian cancer cells. These demonstrate that eIF4E play roles in growth and chemoresistance in ovarian cancer. MEK inhibitor U0126 also significantly enhances chemotherapeutic agents' inhibitory effects. CONCLUSIONS: Our work shows that ERK/Mnk/eIF4E activation is critically involved in ovarian cancer chemoresistance and inhibiting ERK/Mnk/eIF4E broadly sensitizes ovarian cancer response to chemotherapy.
PURPOSE: To investigate whether ERK/MNK/eIF4E contributes chemoresistance in ovarian cancer. METHODS: The phosphorylated levels of Erk, Mnk, and eIF4E were systematically analyzed in ovarian cancerpatients before and after chemotherapy, and ovarian cancer cells exposed to short- and long-term chemo-agent treatment. The roles of Erk/Mnk/eIF4E were investigated using pharmacological and genetic approaches. RESULTS: Increased phosphorylation levels of ERK, Mnk1, and eIF4E were observed in ovarian cancer cell exposed to chemotherapeutic agents, and paclitaxel-resistant SK-OV-3-r cells, and is a common response of ovarian cancerpatients undergoing chemotherapy. MEK inhibitor U0126 inhibits basal and chemodrug-induced phosphorylation of ERK as well as Mnk1 and eIF4E, suggesting that Mnk1/eIF4E are the downstream signaling of ERK pathway and chemotherapy agents activate ERK/MNK/eIF4E in a MEK-dependent manner. eIF4E overexpression promotes ovarian cancer cell growth without affecting migration. In addition, ovarian cancer cells with eIF4E overexpression are more resistant to chemotherapeutic agents in aspect of growth inhibition and apoptosis induction compared to control cells. In contrast, eIF4E depletion augments chemotherapeutic agents' effect in ovarian cancer cells. These demonstrate that eIF4E play roles in growth and chemoresistance in ovarian cancer. MEK inhibitor U0126 also significantly enhances chemotherapeutic agents' inhibitory effects. CONCLUSIONS: Our work shows that ERK/Mnk/eIF4E activation is critically involved in ovarian cancer chemoresistance and inhibiting ERK/Mnk/eIF4E broadly sensitizes ovarian cancer response to chemotherapy.
Entities:
Keywords:
Chemotherapy resistance; ERK; Mnk/eIF4E; Ovarian cancer
Authors: L S Steelman; R A Franklin; S L Abrams; W Chappell; C R Kempf; J Bäsecke; F Stivala; M Donia; P Fagone; F Nicoletti; M Libra; P Ruvolo; V Ruvolo; C Evangelisti; A M Martelli; J A McCubrey Journal: Leukemia Date: 2011-04-15 Impact factor: 11.528
Authors: Jeremy L Yap; Shilpa Worlikar; Alexander D MacKerell; Paul Shapiro; Steven Fletcher Journal: ChemMedChem Date: 2011-01-03 Impact factor: 3.466
Authors: Jessica K Altman; Amy Szilard; Bruce W Konicek; Philip W Iversen; Barbara Kroczynska; Heather Glaser; Antonella Sassano; Eliza Vakana; Jeremy R Graff; Leonidas C Platanias Journal: Blood Date: 2013-03-18 Impact factor: 22.113
Authors: Hans-Guido Wendel; Ricardo L A Silva; Abba Malina; John R Mills; Hong Zhu; Takeshi Ueda; Rie Watanabe-Fukunaga; Rikiro Fukunaga; Julie Teruya-Feldstein; Jerry Pelletier; Scott W Lowe Journal: Genes Dev Date: 2007-11-30 Impact factor: 11.361
Authors: Thao N D Pham; Krishan Kumar; Brian T DeCant; Meng Shang; Samad Z Munshi; Maria Matsangou; Kazumi Ebine; Hidayatullah G Munshi Journal: Mol Cancer Ther Date: 2018-11-16 Impact factor: 6.261
Authors: Qianyu Guo; Vivian Z Li; Jessica N Nichol; Fan Huang; William Yang; Samuel E J Preston; Zahra Talat; Hanne Lefrère; Henry Yu; Guihua Zhang; Mark Basik; Christophe Gonçalves; Yao Zhan; Dany Plourde; Jie Su; Jose Torres; Maud Marques; Sara Al Habyan; Krikor Bijian; Frédéric Amant; Michael Witcher; Fariba Behbod; Luke McCaffrey; Moulay Alaoui-Jamali; Nadia V Giannakopoulos; Muriel Brackstone; Lynne-Marie Postovit; Sonia V Del Rincón; Wilson H Miller Journal: Cancer Res Date: 2019-01-18 Impact factor: 12.701